The objective of this proposal is to explore the relationship of the structure of glucagon to its biological activity. The mechanisms involved must be understood to define the role of hyperglucagonemia in the diabetic patient. The in vivo carbamino glucagon mole fraction will be quantitated over pH and carbon dioxide ranges characteristics of diabetic acidosis and correlated with activity. Native glucagon will be chemically modified at each end, cleaved internally or semisynthesized to include labelled or alternative residues. The derivatives will be studied by chemical analysis, by circular dichroism, by 13C NMR analysis, and the results correlated with binding and activation. Binding will be differentiated from activation. The results will provide better understanding of the relationships of the structure of glucagon for its receptor binding and its adenyl cyclase activation, will be valuable for developing hormone-receptor interaction inhibitors, and will define the role of in vivo acid-base imbalance in the action of glucagon.